The long-range goal of this program is to understand the cellular and molecular bases for the unique trophic and regenerative capacities of chemosensory cells. Key to this is learning how chemosensory systems initially develop, as a wealth of evidence suggests that their trophic and regenerative capacities are due to the retention or re-expression of developmental mechanisms. The continued expression of developmental mechanisms in the adult must require additional, novel mechanisms because critical features of the adult system differ profoundly from that of the embryo. How do chemosensory systems deal with these differences? Knowledge of the strategies used may help us understand how chemosensory systems maintain functional constancy despite turnover and replacement of their transduction cells. The projects of this Program address these kinds of issues. The research centers on several fundamental problem areas. Olfactory transduction has begun to yield its molecular and membrane secrets. Studies in this program will determine how putative olfactory receptor gene families become organized into topographically distinct zones in the epithelium. regulatory sites conferring tissue and zonal specificity will be identified. Both olfactory and taste axons exhibit directional and target specific growth. Experiments will attempt to identify the cellular/molecular cues signals that regulate these specific growth patterns. Olfactory axons stop growing when they reach the olfactory bulb and then begin to express new families of functional molecules. The factors that regulate these target induced changes will be identified. Recent evidence indicates that the turnover and replacement of olfactory neurons is highly regulated. Findings in the last funding period suggest that speCific trophic factors regulate this process. Experiments will identify the transduction pathway of trophic factor actions, characterize the regulation of these factors and test their effectiveness in stimulating the proliferation of olfactory neurons. The mechanisms that regulate the production and orderly differentiation of ORNs have been difficult to identify and experimentally manipulate. The development, in the last funding period, of culture conditions that support the genesis and differentiation of ORNs opens the door to experiments that can determine the mechanisms of ORN differentiation, including their ability to respond selectively to specific odors. Olfactory neurons appear to induce the early development of the olfactory bulb and later, the expression of transmitters in bulb neurons. This trophic dependence continues throughout life as many bulb neurons cease to express their transmitters/peptides after olfactory nerve deafferentation. What is the nature of these regulatory actions? New studies will determine the roles of neural activity and target derived trophic factors in the regulation of dopamine (DA), which is contained approximately 300,000 juxtaglomerular neurons. Taste cells and taste nerves exhibit a spectrum of cell surface molecules, including some of those expressed on olfactory neurons. Are these molecules regulated by signals specific to the location of these cells in the tongue, or by the taste nerves innervating them? The answers to such questions will provide clues about the mechanisms that regulate the orderly turnover and replacement of taste cells New evidence in the last funding period suggests for the first time that there is continuous neural remodeling in normal gustatory brain areas. Experiments here will determine if this remodeling is in response to changes in taste cell-taste nerve connections that result from normal taste cell turnover and replacement.